Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer

The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors.


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Analysis for Table 1 was carried out
The genomic data generated in in this study has been deposited in in AACR Project GENIE cBioPortal under the GENIE cohort public project.The genomic data in in GENIE is is under restricted access that can be be accessed when agreeing to to the terms and conditions of of GENIE use.Clinical molecular, histological, and staging datasets and internally filtered genomic datasets are available in in the Source Data with matching GENIE identifiers.However, only GENIE data has exact mutational data such as as

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All studies must disclose on these points even when the disclosure is negative.Sex was collected for all patients and reported in Table 1.Gender was not included as not applying to this specific genomic analysis.
All the relevant characteristics of the study population were carefully described in Table 1.
All the relevant characteristics of the study population were carefully described in Table 1.
Participants with metastatic breast cancer being treated at Dana-Farber Cancer Institute from July 1, 2013 to December 31, 2020 were approached to have genomic profiling testing performed using next-generation sequencing platform (Oncopanel).
If they provided consent to DF/HCC IRB #11-104 and/or #17-000, we included them in the study if they met inclusion criteria as stated in the manuscipt.
Dana-Farber/Harvard Cancer Center Institutional Review Board Given the retrospective nature of our study, all patients with a sample meeting inclusion criteria in our database were included.
No data that met inclusion criteria was excluded from the study.
Replication was carried out by redoing the analysis in 2 smaller subpopulations of our study cohort.The first was patients that had a sample sequenced after a diagnosis of metastatic disease.The second was to only look at samples that were classified as IHC 0/2+, excluding samples that were classified as IHC 1+.Replication was successful and confirmed that in a more homogeneous population, our findings still held.
As this was a retrospective study, randomization is not relevant as the investigators were not actively altering a variable and could not select which group participants would be selected in.
As this was a retrospective study, blinding is not relevant as the investigators were not actively altering a variable and would not be able to introduce bias through knowledge of participants groups.

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April 2023

Novel plant genotypes
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Describe the methods by which all novel plant genotypes were produced.This includes those generated by transgenic approaches, gene editing, chemical/radiation-based mutagenesis and hybridization.For transgenic lines, describe the transformation method, the number of independent lines analyzed and the generation upon which experiments were performed.For gene-edited lines, describe the editor used, the endogenous sequence targeted for editing, the targeting guide RNA sequence (if applicable) and how the editor was applied.was applied.was applied.
Report on the source of all seed stocks or other plant material used.If applicable, state the seed stock centre and catalogue number.If plant specimens were collected from the field, describe the collection location, date and sampling procedures.
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using the existing OncoPanel bioinformatics pipeline that has been described in in detail.More details can be be found in in the submitted manuscript and at: Sholl et et al., JCI Insight 2016, Ramkisoon et et al., Neuro Oncology 2017, Hanna et et al., JC JC Insight 2017 Analysis was carried out using the R statistical software package and Python and associated packages.Python version 3.10 with statsmodel package 0.13.1 and CMH package 1.0.1 and R version 4.3.1 and coin package 1.4.3 were used.
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